A KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma

Windon, Annika; Loaiza‐Bonilla, Arturo; Jensen, Christopher E.; Randall, Michael P.; Morrissette, Jennifer J.D.; Shroff, Stuti G.

doi:10.21037/jgo.2017.10.14

Cited by 46 publications

(42 citation statements)

References 41 publications

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“…Moreover, Kim and colleagues reported that PDAC patients with KRAS mutations display a worse response to gemcitabine-based chemotherapy and shorter overall survival than those with KRAS wild-type [ 27 ]. Along the same lines, Windon and colleagues confirmed a survival disadvantage for KRAS mutant patients, showing that such adverse prognostic effect was independent of mismatch repair status and the specific chemotherapy regimen employed [ 28 ]. These findings warrant further investigation, as they may support new strategies for implementing precision oncology in PDAC patients.…”

Section: Introductionmentioning

confidence: 98%

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Luchini

Paolino

Mattiolo

et al. 2020

J Exp Clin Cancer Res

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Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases. The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group. This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.

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Section: Introductionmentioning

confidence: 98%

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Luchini

Paolino

Mattiolo

et al. 2020

J Exp Clin Cancer Res

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“…Deletion of CDKN2A and KRAS mutations were reported as adverse prognostic markers throughout a plethora of diverse malignancies . Thus, poor prognosis associated with CDKN2A deletion and KRAS activation appears as a recurrent feature of a broad spectrum of malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…12 Deletion of CDKN2A and KRAS mutations were reported as adverse prognostic markers throughout a plethora of diverse malignancies. [21][22][23][24][25][26][27][28][29] Thus, poor prognosis associated with CDKN2A deletion and KRAS activation appears as a recurrent feature of a broad spectrum of malignancies. As CUP may arise from any organ site, it is plausible that these negative prognostic effects observed in other cancer entities are also reflected in CUP.…”

Section: Discussionmentioning

confidence: 99%

Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary

Bochtler

Reiling

Endris

et al. 2020

Intl Journal of Cancer

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Cancer of unknown primary (CUP) denotes a malignancy with histologically confirmed metastatic spread while the primary tumor remains elusive. Here, we address prognostic and therapeutic implications of mutations and copy number variations (CNVs) detected in tumor tissue in the context of a comprehensive clinical risk assessment. Targeted panel sequencing was performed in 252 CUP patients. 71.8% of patients had unfavorable CUP according to ESMO guidelines. 74.7% were adeno‐ and 13.7% squamous cell carcinomas. DNA was extracted from microdissected formalin‐fixed, paraffin‐embedded tissues. For library preparation, mostly multiplex PCR‐based Ion Torrent AmpliSeq™ technology with Oncomine comprehensive assays was used. Most frequent genetic alterations were mutations/deletions of TP53 (49.6%), CDKN2A (19.0%) and NOTCH1 (14.1%) as well as oncogenic activation of KRAS (23.4%), FGFR4 (14.9%) and PIK3CA (10.7%). KRAS activation was predominantly found in adenocarcinomas (p = 0.01), PIK3CA activation in squamous cell carcinomas (p = 0.03). Male sex, high ECOG score, unfavorable CUP, higher number of involved organs and RAS activation predicted decreased event‐free and overall survival in multivariate analysis. Deletions of CDKN2A were prognostically adverse regarding overall survival. TP53 mutations did not significantly influence prognosis in the overall cohort, but worsened prognosis in otherwise favorable CUP subtypes. Although not standard in CUP, for 17/198 (8.6%) patients molecularly targeted treatment was recommended and 10 patients (5.1%) were treated accordingly. In conclusion, besides the identification of drug targets, panel sequencing in CUP is prognostically relevant, with RAS activation and CDKN2A deletion emerging as novel independent risk factors in a comprehensive assessment with clinicopathological data.

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“…Recently, our group has reported that DPYD*9A (c.85T>C) variant was the most common variant diagnosed in our cohort and a genotype-clinical phenotype correlation was noticeable. All patients who received full dose fluoropyrimidines experienced grade 3-4 diarrhea [15,16]. Other group have also reported the correlation between DPYD*9A (c.85T>C) and grade 3-4 toxicity [8,10,11].…”

Section: Editorialmentioning

confidence: 99%

Revisiting the Clinical Importance of DPYD*9A (c.85T>C) Variant of Dihydropyrimidine Dehydrogenase (DPYD) Gene in Patients Treated with Fluoropyrimidine-Based Chemotherapy

Patel

Taylor

Singh

et al. 2018

J Mol Biomark Diagn

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A KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma

Cited by 46 publications

References 41 publications

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary

Revisiting the Clinical Importance of DPYD*9A (c.85T>C) Variant of Dihydropyrimidine Dehydrogenase (DPYD) Gene in Patients Treated with Fluoropyrimidine-Based Chemotherapy

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